Triazole compounds useful in treating diseases associated with unwanted cytokine activity

Abstract

The present invention relates to 4-aryl triazoles having the formula:wherein R<1 >is independently selected from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lower heteroalkenyl, lower heteroalkynyl, heterocycloalkyl, heteroaryl, halo, CN, OR<4>, SR<4>, S(O)R<4>, S(O)2R<4>, and NR<4>R<5>; and Q is has the general formula:said compounds are useful in treating diseases associated with unwanted cytokine activity, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells.

What is claimed is:  
     
       1. A compound having the formula:                    
       wherein R 1  is chosen from fluoro and chloro;  
       R 4  is chosen from hydrogen, methyl, isopropyl, phenyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-fluorobenzyl (S)-1-phenylethyl, and (R)-1-phenylethyl;  
       A and B are each chosen from methylcarbonyl, furan-2-ylcarbonyl, phenylcarbonyl, 4-methoxyphenylcarbonyl, 4-chlorophenylcarbonyl, ethoxycarbonyl, phenylthio-thiocarbonyl, phenylmethoxycarbonyl 2-methoxyethoxycarbonyl methoxymethyl,(2-methoxyethoxy)-methyl, phenylmethoxymethyl, 2-methoxymethyl, 2-ethoxymethyl, 2-phenoxyethyl, methylsulfonyl, pheylsulfonyl, 2-furansulfonyl, N-ethyl-N-phenylaminocarbonyl, 2,3-dihydroindol-1-ylcarbonyl, N,N-dimethylaminocarbonyl, tetrahydrofuranyl-N-carbonyl, morpholino-N-carbonyl, piperidyl-N-carbonyl, pyrrol-2-ylcarbonyl and pyrrol-3-carbonyl.  
     
     
       2. A compound according to  claim 1  chosen from: 
       4-(4-Fluorophenyl)-5-[2-(phenylmethylamino)pyrimidin-4-yl)-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-aminopyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(iso-propylamino)pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(phenylamino)pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(4-methylphenylmethylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(4-methoxyphenylmethylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(4-fluorophenylmethylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(S)-phenylethylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-methoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-[(2methoxyethoxy)-methyl]-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(phenylmethoxymethyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2-methoxyethyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2-ethoxyethyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2-phenoxyethyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-methylsulfonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-phenylsulfonyl-[1,2,3]triazole;  
       4-(4-chlorophenyl)-5-[2-(phenylemthylamino)-pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       5-(4-chlorophenyl)-4-[2-(phenylmethylamino)pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(3-trifluoromethylphenyl)-5-[2-(phenylmethylamino)pyrimidin-4-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-fluorophenyl)-5-(2-aminopyrimidin-4-yl)-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(4-methylphenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(4-methoxyphenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1 -phenylethylamino)-pyrimidin-4-yl-1-(3,4-dimethoxyphenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-[4-(2-methoxyethoxy)-phenyl]-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(4-phenoxyphenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-[4-(N,N-dimethylamino)-phenyl]-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(4-chlorophenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(3-fluorophenyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(4-methylsulfinylphenyl)-[1,2,3]triazole; and  
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-[4-(methoxycarbonyl)-phenyl]-[1,2,3]triazole.  
     
     
       3. A compound according to  claim 1  chosen from: 
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(piperidyl-N-carbonyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(tetrahydrofuran-4-ylcarbonyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(pyrrol-2-ylcarbonyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(pyrrol-3-ylcarbonyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(tetrahydrofuran-4-yl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(tetrahydrofuran-4-ylmethyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl]-1-(2-aminoethyl)-[1,2,3]triazole;  
       (S)-4-(4-fluorophenyl)-5-[4-(1-phenylethylamino)-pyrimidin-6-yl]-1-ethoxymethyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2-furansulfonyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(N-ethyl-N phenylaminocarbonyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2,3,dihydro-indol-1-ylcarbonyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]—(N,N-dimethylaminocarbonyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(tetrahydrofuranyl-N-carbonyl)-[1,2,3]triazole; and  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(morpholino-N-carbonyl)-[1,2,3]triazole.  
     
     
       4. A compound according to  claim 1  chosen from: 
       4-(4-Fluorophenyl)-5-[2-(1-phenylethylamino)-pyrimidin-4-yl-1-(benzo[1,3]dioxol-5-yl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-methylcarbonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(furan-2-ylcarbonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-phenylcarbonly-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-4-methoxyphenyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-4-chorophenylcarbonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-ethoxycarbonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(phenylthio-thiocarbonyl)-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-phenylmethoxycarbonyl-[1,2,3]triazole;  
       4-(4-Fluorophenyl)-5-[2-(R)-phenylethylamino)-pyrimidin-4-yl]-1-(2-methoxyethoxy-[1,2,3]triazole.  
     
     
       5. A pharmaceutical composition comprising: 
       (a) a safe and effective amount of a compound of  claim 1 ; and  
       (b) a pharmaceutically-acceptable carrier.  
     
     
       6. A method for treating a disease associated with unwanted cytokine activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 1 . 
     
     
       7. The method according to  claim 6  wherein the disorder is osteoarthritis. 
     
     
       8. The method according to  claim 6  wherein the disorder is rheumatoid arthritis. 
     
     
       9. The method according to  claim 6  wherein the disorder is congestive heart failure.